Table 2 Summary of tendon injury models
Injured Tendon Characteristics | Model Characteristics | Model Outcomes | References |
|---|---|---|---|
Overuse injury | Downhill running in rats | Induced overuse injury in the supraspinatus | Soslowsky 2000 [107] Archaumbault 2006 [108] |
Bipedal downhill running in rats | Reduced stiffness and tensile strength; localized disintegration of collagen bundles | Ng 2011 [109] | |
Uphill running in rats | Achilles tendons adapted to loading; no observable pathology | Heinemeier 2012 [110] Dirks 2013 [111] | |
Transection/Acute injury | Neonatal and adult mouse Achilles tendons | Regeneration observed in neonates, but not adults | Howell 2017 [112] |
Mouse supraspinatus tendons with full and partial transections | Different cell populations involved in healing of full versus partial injury; distinct cell lineages participate in healing response | Moser 2018 [113] Yoshida 2016 [114] | |
Rat Achilles tendon partial transection repaired with scaffolds | Cells in scaffolds expressed mohawk during repair | Otabe 2015 [32] | |
Mouse Achilles tendon full transections repaired with MSC sheets overexpressing mohawk | Mohawk-overexpressing MSC sheets resulted in increased collagen fibril diameter, visible crimp, increased stiffness, elastic modulus, maximum force and stress, and energy absorbed | Liu 2015 [31] | |
Canine digital flexor tendons | Following injury, IL-1β upregulated 4000-fold, MMP-13 upregulated 24,000-fold | Manning 2014 [115] | |
IL-1β treatment | E15 and P7 mouse tendon cells treated with IL-1β | Higher expression of IL-6, TNFα, COX2, MMP-3 and MMP-13 in P7 compared to E15 | Li 2019 [116] |
Human patellar tendon fibroblasts treated with IL-1β and strain | IL-1β and 8% strain upregulated MMP-1, COX2, and PGE2; IL-1β and 4% strain downregulated expression of MMP-1, COX2, and PGE2 compared to 8% strain | Yang 2005 [117] | |
Adult and fetal equine tendon cells, and equine embryonic stem cells treated with IL-1β | Adult and fetal tendon cells upregulated MMP-1, −2, −3, −8, −9, and − 13, tenascin-C, Sox9, and downregulated scleraxis and COMP, compared to embryonic stem cells | McClellan 2019 [118] | |
Genetic knockouts | Tenomodulin knockout mice with transected and repaired Achilles tendons | Downregulation of Col I, tenascin-C, thrombospondin 2, and TGFβ1; upregulation of scleraxis, COMP, and proteoglycan 4 | Lin 2017 [119] |
GDF-5 knockout mice subjected to Achilles tendon injury | Delayed healing and increased adipocytes in knockouts | Chhabra 2003 [120] | |
Decorin-null and biglycan-null mice subjected to full thickness, partial width patellar tendon injury in adult and aged groups | Smaller diameter collagen fibrils, decreased cell density, and altered cell shape and collagen alignment in knockouts; biglycan influenced early healing, decorin influenced late healing | Dunkman 2014 [121] Dunkman 2014 [122] | |
Chronic Injury/Induced Tendinopathy | Transection or Botox-unloading of rat Achilles tendon | Irreversible loss of scleraxis expression with transection; partial loss and return of scleraxis with Botox | Maeda 2011 [123] |
Immediate or delayed repair of rat rotator cuff injury | Delayed repair had worse outcomes than immediate repair | Killian 2014 [124] | |
TGFβ1 injection to rat Achilles | Warburg pathway, hypoxic, angiogenic, and glycolytic metabolism gene activation | Sikes 2018 [125] | |
Collagenase injection in rat Achilles tendon | Increased IL-6 and MMP-9 in senescence-accelerated rats compared to senescence-resistant rats | Ueda 2019 [126] | |
Carrageenan injection in rat patellar tendon; treatment with IL-1 receptor antagonist | Carrageenan decreased tendon length, and increased MMP activity and inflammation. Inflammation absent with IL-1 receptor antagonist | Berkoff 2016 [127] | |
Ex vivo Loading | Stress deprivation in rat tail tendons | Increased MMP-13 expression | Arnoczky 2007 [128] |
Stress deprivation in rat tail tendons | Stress deprivation decreased TIMP/MMP ratio; loading increased TIMP/MMP ratio | Gardner 2008 [129] | |
Fatigue loading of rat flexor digitorum longus tendon loaded at low (6.0–7.0%), moderate (8.5–9.5%), and high (11.0–12.0%) tensile strain | Isolated fiber deformations at low strain; fiber dissociation and localized rupture, decreased stiffness, and increased hysteresis at high strain | Fung 2009 [130] | |
Equine flexor and extensor tendon cells subjected to 10% biaxial cyclic loading | Collagen synthesis, proliferation, COMP expression as a function of tendon type | Goodman 2004 [131] | |
Equine superficial digital flexor tendon fascicles cyclically loaded from 2–12% uniaxial strain and 1800 cycles | Increased expression of IL-6, COX2, C1, C2, and MMP-13 | Thorpe 2015 [132] | |
Bovine deep digital flexor tendons cyclically loaded from 1 to 10% strain | Collagen fiber disruption, kinks, and interfascicular network damage, and expression of IL-6, COX2, MMP-1, 3, and 13 | Spiesz 2015 [48] | |
Mouse patellar tendon cells isolated from 3-week old mohawk knockouts and subjected to 4% cyclic tensile loading | Increased chondrogenic gene expression (Col II, Aggrecan, COMP) | Suzuki 2016 [47] | |
Computational models | Cell- and tissue-level responses to strain simulated via Hill functions | Tissue-level response similar at low and high strain conditions | Mehdizadeh 2017 [133] |
Hill-type equations of human Achilles-soleus unit | Proteolytic damage leads to collagen fiber shortening; mechanical damage lengthens fibers | Young 2016 [134] | |
Regression model of healing | Multiple differential predictors of early development and early developmental healing; however, no differential predictors of late development and late developmental healing | Ansorge 2012 [135] | |
2D FEA simulation of “jumper’s knee” in Patellar tendon | Highest localized strain predicted successfully | Lavagnino 2008 [136] | |
Agent-based model of collagen fibril alignment with applications in tendon loading during healing | Peak collagen alignment occurs at lower strain level than peak deposition; peak deposition occurs above damage threshhold | Richardson 2018 [137] | |
Multiscale OpenSim model of cellular responses to various loading parameters | Single set of cellular response curves explained tendon behavior observed in several different experiments | Chen 2018 [138] | |
Empirical model of patellar tendon response to aging and injury | Effects of aging and injury on patellar tendon mechanical properties predicted by damage models | Buckley 2013 [139] | |
Empirical model of Achilles tendon response to decorin and biglycan knockout in aging mice | Model predicted changes in dynamic modulus resulting from decorin and biglycan knockout | Gordon 2015 [140] |